Among white men, serum estradiol exerts a “robust causal effect” on fracture risk, independent of age, BMI, smoking status and physical activity level, according to findings from a large Mendelian randomization analysis.

Claes Ohlsson

In an analysis of genome-wide association study data from men participating in the UK Biobank, the researchers also found no causal link between testosterone levels and estimated bone mineral density, a predictor of fracture risk.

“Based on the findings in the present study, one may speculate that treatments augmenting serum estradiol, such as testosterone supplementation, may reduce fracture risk in men,” Claes Ohlsson, MD, PhD, professor at the Institute of Medicine and director of the Centre for Bone and Arthritis Research at Sahlgrenska Academy, University of Gothenburg, Sweden, told Endocrine Today. “However, to avoid androgen receptor-related side effects, one might consider bone-specific selective estrogen receptor modulators to reduce fracture risk in men. In addition, our findings indicate that nonaromatizable androgens, not augmenting estradiol, will be inefficient in reducing fracture risk in men.”

Ohlsson and colleagues analyzed genome-wide association study data from 175,583 men aged 37 to 76 years participating in the UK Biobank, including estradiol- and testosterone-associated single nucleotide polymorphisms. Researchers estimated BMD using quantitative ultrasound of the heel and self-reported fractures in select participants (n = 17,650).

The researchers noted that a low number of hip and spine fractures precluded separate hip and spine fracture analyses. Researchers did not observe a causal link between testosterone levels and fracture risk.

In an interview, Ohlsson said the finding of a causal effect of serum estradiol, but not testosterone, on fracture risk might also be of importance for estimating possible skeletal side effects of endocrine therapies in men with prostate cancer.

“Our findings suggest that chemical castration with [gonadotropin-releasing hormone] agonists, as well as CYP17 inhibition using abiraterone, will result in increased fracture risk in these patients, since both treatments will reduce serum testosterone as well as serum estradiol levels,” Ohlsson said. “This notion is supported by a substantially increased fracture risk in prostate cancer patients after chemical castration. In contrast, our data, showing no causal effect of testosterone on fracture risk, indicate that endocrine prostate cancer treatment with the specific androgen receptor antagonist enzalutamide (Xtandi; Astellas, Pfizer) could avoid these skeletal side effects.” – by Regina Schaffer

Disclosures: The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF research grant in Gothenburg, the Lundberg Foundation, Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Soderberg’s Foundation and the Novo Nordisk Foundation supported this study. The authors report no relevant financial disclosures.

Perspective

Perspective

Sex steroids unequivocally influence skeletal health in boys and men. During growth and adolescence, both estrogens and androgens are critical for the development of normal peak bone mass and structure. Hypogonadism in adult men has adverse effects on bone density and increases fracture risk, and testosterone replacement (which increases both testosterone and estradiol levels) has positive effects on bone. Also, the decline in sex steroids with aging has been tied to increased bone loss and fractures. However, in adult men some controversy has remained concerning the relative importance of androgens vs estrogens in maintaining bone health. Carefully done, short-term experiments of selective androgen or estrogen deprivation in men have revealed effects of both, with the effects of estrogen being more robust. Moreover, longitudinal cohort studies suggest estradiol has a more obvious beneficial effect than testosterone.

Recently, Nethander and colleagues bring even more evidence to support the essential role of estrogens in the male skeleton. They took advantage of genotyping in the UK Biobank and the unique strategy of Mendelian randomization (MR). The principle of MR rests on the understanding that if a factor (in this case, serum estradiol or testosterone) influences an outcome (in this case, BMD or fracture), then the genetic determinates of the factor should also be associated with the outcome. The MR study design takes out of the research equation some thorny problems like the accuracy of serum sex steroid measurements and the possibility that there are unknown confounding factors that might affect sex steroid levels and bone health independently. In fact, in their study the genetic variants that affect estradiol were associated with both BMD and fracture risk in men. This is powerful, independent evidence of a causal link between estradiol and bone health in men. On the other hand, the genetic variants that influence testosterone levels were not associated with BMD or fracture risk.

These results are important for several reasons. They argue very persuasively that estradiol is important, and probably more important than testosterone, for preserving bone health in men. In practical terms, they suggest that therapies that selectively reduce testosterone, but not estradiol, may preserve bone health — for instance, in androgen deprivation therapy for prostate cancer. Also, they argue for the potential benefit of estradiol measures in assessing osteoporosis risk in men, rather than the usually recommended testosterone measurements. Overall, the use of MR represents a clever technique that further cements the dominant role of estrogen in bone health in adult men